Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • ASCI Milestone Awards
    • Video Abstracts
    • Conversations with Giants in Medicine
  • Reviews
    • View all reviews ...
    • Clinical innovation and scientific progress in GLP-1 medicine (Nov 2025)
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • ASCI Milestone Awards
  • Video Abstracts
  • Conversations with Giants in Medicine
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Notch signaling dynamically regulates adult β cell proliferation and maturity
Alberto Bartolome, Changyu Zhu, Lori Sussel, Utpal B. Pajvani
Alberto Bartolome, Changyu Zhu, Lori Sussel, Utpal B. Pajvani
View: Text | PDF
Research Article Endocrinology Metabolism

Notch signaling dynamically regulates adult β cell proliferation and maturity

  • Text
  • PDF
Abstract

Notch signaling regulates differentiation of the pancreatic endocrine lineage during embryogenesis, but the role of Notch in mature β cells is unclear. We found that islets derived from lean mice show modest β cell Notch activity, which increases in obesity and in response to high glucose. This response appeared maladaptive, as mice with β cell–specific–deficient Notch transcriptional activity showed improved glucose tolerance when subjected to high-fat diet feeding. Conversely, mice with β cell–specific Notch gain of function (β-NICD) had a progressive loss of β cell maturity, due to proteasomal degradation of MafA, leading to impaired glucose-stimulated insulin secretion and glucose intolerance with aging or obesity. Surprisingly, Notch-active β cells had increased proliferative capacity, leading to increased but dysfunctional β cell mass. These studies demonstrate a dynamic role for Notch in developed β cells for simultaneously regulating β cell function and proliferation.

Authors

Alberto Bartolome, Changyu Zhu, Lori Sussel, Utpal B. Pajvani

×

Figure 5

Notch activation and reduced maturity in proliferating β cells.

Options: View larger image (or click on image) Download as PowerPoint
Notch activation and reduced maturity in proliferating β cells.
(A) Repr...
(A) Representative images of pancreatic sections from day 15 (D15) pregnant (D15) WT mice and quantitation expressed as average MafA fluorescence intensity of BrdU+ and BrdU– populations (n = 5 mice/group). Individual cells are plotted in Supplemental Figure 6A. (B) Representative images of pancreatic sections from pregnant (D15) mice stained for BrdU as well as antibodies directed against insulin and Pdx1, Neurod1, or Ucn3 (n = 5 mice/group). (C) Representative images of pancreatic sections from virgin and pregnant (D15) TNR mice, with quantitation of percentage of GFP+ β cells (n = 4–5 mice/group). (D) Representative images of pancreatic sections from pregnant (D15) TNR mice showing Ki67, insulin, and GFP reporter staining (top), with increased magnification of the boxed region (bottom). Arrows indicate Ki67+ β cells. Quantitation of percentage of GFP+ β cells or percentage of GFP+Ki67+ β cells (n = 5 mice/group; overall count of 3995 total β cells and 188 Ki67+ β cells). (E) Quantitation of average MafA fluorescence intensity in GFP– and GFP+ β cells from chow-fed TNR mice, normalized to average value in GFP– cells (n = 5 mice). Approximately 1000 cells quantified per pancreas. Scale bars: 20 μm. All data are shown with group means. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed t test.

Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts